Failure of passive transfer (FPT) occurs when a newborn calf does not absorb enough antibodies (<10 g/l of IgG) from the colostrum. Some calves absorb antibodies very effectively while others do not. This difference in uptake cannot be explained solely by the time, amount and quality of the colostrum given. Natural antibodies (NAb) are produced without any antigenic stimulation and target self-antigens and pathogen-associated molecular patterns (PAMPs). Our objective was to estimate genetic parameters and detect quantitative trait loci (QTL) for three NAb isotypes (IgG, IgM and IgA) in newborn calf serum binding keyhole limpet hemocyanin (KLH) and muramyl dipeptide (MDP). Two experimental farms were included in the study. Serum samples were collected from 831 calves between 2 to 7 days old, born from January 2015 to April 2017. 70% of the animals were Swedish Red and 30% Swedish Holstein. Antibodies were measured from serum using indirect ELISAs. To estimate genetic parameters, a linear mixed model was run, correcting for antibody concentration of colostrum given, volume of first meal, time of birth to blood sampling time, weight at birth and breed, including genetic effect, maternal effect and Herd-Year-Season of calving with sample storage plate as random effects. An imputed 50K SNP array from a LD 7K array was used for the Genome-wide association study (GWAS), running the same model but including the SNP genotype as a fixed effect. Heritabilities for NAb isotypes in newborn calf serum ranged from 0.20 to 0.53, with a maternal effect ranging from 5 to 30%. Genetic correlations between IgM and IgA ranged from 0.74 to 0.94. The GWAS revealed one QTL on BTA1 for MDP-IgG, comprised of 3 SNPs (-log10(p) = 5.9), one significant and two suggestive, ranging from 1-8 Mbp and another QTL on BTA3 for IgM (KLH and MDP) consisting of 2 suggestive SNPs (-log10(p) = 5.02), from 13-25 Mbp. Our results suggest that natural antibodies can potentially provide an effective tool to reduce FPT using genetic selection.